Discussion
In a detailed and comprehensive account of the Pediatric Official
Positions of the International Society of Clinical
Densitometry24 on quantitative computer tomography,
Adams et al addressed the preferred choice of the non-dominant limb and
the selection of sampling sites, including the 4% and 20% radius in
addition to the 4%, 38% and 66% tibia as used in this study.
While the findings reported here suggest that, overall, the subjects,
long term survivors of ALL in childhood and adolescence, exhibit mainly
normal bone health, comparison with data from healthy populations has to
be made with due consideration for important differences in their
characteristics. For example, as reported by Leonard and colleagues at
the Children’s Hospital of Philadelphia (CHOP)16 in a
large group of healthy children, adolescents and young adults in the US,
the racial composition of the study sample is critical. African
Americans have higher values than Whites for numerous cortical measures
at the 38% tibia which are reflected in a 13% greater average for the
polar section modulus metric of bone strength. Similar differences exist
between males and females.16 Comparable findings have
been published from South Africa with bone strength measured by polar
SSI.30 These authors have reviewed the international
experience of the influence of ethnicity on bone.31Consequently, the comparison of our study sample with a reference group
of healthy subjects of the same ethnicity provides a more accurate
assessment of their bone health. This reveals deficits in the
mineralization of trabecular bone at the distal radial metaphysis in
more than one third of subjects with a less consistent pattern in the
corresponding tibia. Deficits in the mid-shaft of the tibia, except for
cortical vBMD, are associated with reduced bone strength in almost one
third of subjects.
Our findings of great total and trabecular vBMD in males than in females
at the metaphyseal sites have been reported in healthy older
adolescents.21,22
A seemingly counter-intuitive finding in the current study is the
greater cortical thickness at the 38% than at the 66% tibial sites.
However, in a remarkably detailed investigation conducted in 60 healthy
young adults, pQCT was performed at 14 levels ranging in 5% increments
from the 10% to the 80% sites on the tibia (and the
fibula).32 The cortical thickness was substantially
greater at the 40% than at the 65% tibial sites. Again, in concert
with the current findings, the cross-sectional moments of inertia,
measures of the stiffness of bone in relation to bending, were
progressively greater proximally along the tibial shaft beyond the 30%
site.
Although there are few reports of the use of pQCT to assess bone health
in survivors of ALL in childhood, two are especially informative.
Investigators in Manchester, UK studied 53 school-aged children and
adolescents who had completed treatment, without cranial irradiation,
1.5 to 8.3 years earlier.33 Measurements were made at
the 4% and 50% sites of the non-dominant radius and comparisons were
made with close to 200 healthy subjects in the same age group; a cohort
which grew to 500 in later years,34 affording the
opportunity to develop Z scores (though not applied earlier to the ALL
group). The subjects who had survived ALL had lower trabecular but not
total vBMD than the control group and the deficit was less the longer
the interval from the completion of therapy in this cross-sectional
study. Findings at the diaphyseal site suggested endosteal bone loss
during treatment.
In rather the reverse order, the investigators at CHOP built a reference
cohort of more than 650 individuals, affording the opportunity to
provide Z scores for clinical populations.18Subsequently they were able to study 50 survivors of ALL, ages 5-22
years, within two years of completing treatment which did not include
cranial irradiation.35 Measurements were made at the
3%, 38% and 66% sites of the non-dominant tibia. Trabecular vBMD (at
the 3% site) and cortical vBMD (at the 38% site) were significantly
lower than in the reference group; no results were reported for total
vBMD at either site. When studied one year later both measures showed
improvement but were still significantly lower than in the reference
group. The finding at the metaphysis is comparable to that reported by
Brennan et al,13 but the diaphyseal measurements are
not comparable because the sites are much different.
Our findings with post-processing of images point to greater
connectivity in and more compact trabecular bone in SR than HR
survivors.This may reflect the higher intensity of osteotoxic
chemotherapy in the HR group.
The limitations of this cross-sectional observational study include a
small sample size, although larger than the other published studies of
pQCT in children who had ALL. Again, the subjects had a wide age span
(15 years) and a wide range of time from diagnosis, averaging 15 years,
although all were more than 10 years from that date. A longitudinal
study would be useful, building on the experience of Leonard and
colleagues.17 Addressing the lack of ethnic diversity
in our subjects would require a much bigger sample size.
A particular strength of the study is the use of post-processing with
custom software which expands information on apparent bone architecture
compared to conventional pQCT. A prospective serial study of children
with ALL, along their cancer journey from diagnosis to long term
survivorship, using this technology would provide a detailed picture of
osteotoxicity and recovery while offering opportunities for early
therapeutic intervention to maximize ultimate bone health in this young
population.
Conflict of Interest Statement. The authors have no conflict of interest
to declare